Suppressor role of activating transcription factor 2 (ATF2) in skin cancer

*Burnham Institute for Medical Research, La Jolla, CA 92037;
^†Paterson Institute for Cancer Research, University of Manchester, Manchester M20 4BX, United Kingdom;
Departments of ^‡Medicine and
^¶Dermatology, Yale University School of Medicine, New Haven, CT 06520; and
^§Genetics Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892

Edited by Peter Erich Angel, Deutsches Krebsforschungszentrum, Heidelberg, Germany, and accepted by the Editorial Board November 16, 2007 (received for review June 27, 2007)

Abstract

Activating transcription factor 2 (ATF2) regulates transcription in response to stress and growth factor stimuli. Here, we use a mouse model in which ATF2 was selectively deleted in keratinocytes. Crossing the conditionally expressed ATF2 mutant with K14-Cre mice (K14.ATF2^f/f) resulted in selective expression of mutant ATF2 within the basal layer of the epidermis. When subjected to a two-stage skin carcinogenesis protocol [7,12-dimethylbenz[a]anthracene/phorbol 12-tetradecanoate 13-acetate (DMBA/TPA)], K14.ATF2^f/f mice showed significant increases in both the incidence and prevalence of papilloma development compared with the WT ATF2 mice. Consistent with these findings, keratinocytes of K14.ATF2^f/f mice exhibit greater anchorage-independent growth compared with ATF2 WT keratinocytes. Papillomas of K14.ATF2^f/f mice exhibit reduced expression of presenilin1, which is associated with enhanced β-catenin and cyclin D1, and reduced Notch1 expression. Significantly, a reduction of nuclear ATF2 and increased β-catenin expression were seen in samples of squamous and basal cell carcinoma, as opposed to normal skin. Our data reveal that loss of ATF2 transcriptional activity serves to promote skin tumor formation, thereby indicating a suppressor activity of ATF2 in skin tumor formation.

Footnotes

^‖To whom correspondence should be addressed. E-mail: ronai{at}burnham.org
Author contributions: A.B., B.F., and Z.R. designed research; A.B., B.F., and C.D., performed research; W.B. and N.J. contributed new reagents/analytic tools; A.B., B.F., W.B., H.M.K., S.D., A.S., P.M., S.K., N.J., and Z.R. analyzed data; and A.B. and Z.R. wrote the paper.
The authors declare no conflict of interest.
This article is a PNAS Direct Submission. P.E.A. is a guest editor invited by the Editorial Board.
Data deposition: The data reported in this paper have been deposited in the Gene Expression Omnibus (GEO) database www.ncbi.nlm.nih.gov/geo (accession no. GSE9328).
This article contains supporting information online at www.pnas.org/cgi/content/full/0706057105/DC1.